Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2B7OGB)

• DOT Name: Cyclin-dependent kinase 9 (CDK9)
• Synonyms: EC 2.7.11.22; EC 2.7.11.23; C-2K; Cell division cycle 2-like protein kinase 4; Cell division protein kinase 9; Serine/threonine-protein kinase PITALRE; Tat-associated kinase complex catalytic subunit
• Gene Name: CDK9
• UniProt ID: CDK9_HUMAN
• PDB ID: 3BLH; 3BLQ; 3BLR; 3LQ5; 3MI9; 3MIA; 3MY1; 3TN8; 3TNH; 3TNI; 4BCF; 4BCG; 4BCH; 4BCI; 4BCJ; 4EC8; 4EC9; 4IMY; 4OGR; 4OR5; 5L1Z; 6CYT; 6GZH; 6W9E; 6Z45; 7NWK; 8K5R
• EC Number: 2.7.11.22; 2.7.11.23
• Pfam ID: PF12330 ; PF00069
• Sequence:
  MAKQYDSVECPFCDEVSKYEKLAKIGQGTFGEVFKARHRKTGQKVALKKVLMENEKEGFP
  ITALREIKILQLLKHENVVNLIEICRTKASPYNRCKGSIYLVFDFCEHDLAGLLSNVLVK
  FTLSEIKRVMQMLLNGLYYIHRNKILHRDMKAANVLITRDGVLKLADFGLARAFSLAKNS
  QPNRYTNRVVTLWYRPPELLLGERDYGPPIDLWGAGCIMAEMWTRSPIMQGNTEQHQLAL
  ISQLCGSITPEVWPNVDNYELYEKLELVKGQKRKVKDRLKAYVRDPYALDLIDKLLVLDP
  AQRIDSDDALNHDFFWSDPMPSDLKGMLSTHLTSMFEYLAPPRRKGSQITQQSTNQSRNP
  ATTNQTEFERVF
• Function: Protein kinase involved in the regulation of transcription. Member of the cyclin-dependent kinase pair (CDK9/cyclin-T) complex, also called positive transcription elongation factor b (P-TEFb), which facilitates the transition from abortive to productive elongation by phosphorylating the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A, SUPT5H and RDBP. This complex is inactive when in the 7SK snRNP complex form. Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR and the negative elongation factors DSIF and NELFE. Regulates cytokine inducible transcription networks by facilitating promoter recognition of target transcription factors (e.g. TNF-inducible RELA/p65 activation and IL-6-inducible STAT3 signaling). Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis. P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export. Modulates a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3; integrates phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing. The CDK9/cyclin-K complex has also a kinase activity towards CTD of RNAP II and can substitute for CDK9/cyclin-T P-TEFb in vitro. Replication stress response protein; the CDK9/cyclin-K complex is required for genome integrity maintenance, by promoting cell cycle recovery from replication arrest and limiting single-stranded DNA amount in response to replication stress, thus reducing the breakdown of stalled replication forks and avoiding DNA damage. In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6. Promotes cardiac myocyte enlargement. RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription. AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect. The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation. Catalyzes phosphorylation of KAT5, promoting KAT5 recruitment to chromatin and histone acetyltransferase activity.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Viral life cycle - HIV-1 (hsa03250)
  Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  Formation of HIV elongation complex in the absence of HIV Tat (R-HSA-167152)
  Formation of HIV-1 elongation complex containing HIV-1 Tat (R-HSA-167200)
  Pausing and recovery of Tat-mediated HIV elongation (R-HSA-167238)
  Tat-mediated HIV elongation arrest and recovery (R-HSA-167243)
  Tat-mediated elongation of the HIV-1 transcript (R-HSA-167246)
  HIV elongation arrest and recovery (R-HSA-167287)
  Pausing and recovery of HIV elongation (R-HSA-167290)
  Interactions of Tat with host cellular proteins (R-HSA-176034)
  SMAD2/SMAD3 (R-HSA-2173796)
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  RNA polymerase II transcribes snRNA genes (R-HSA-6807505)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Cyclin-dependent kinase 9 (CDK9) decreases the response to substance of Afimoxifene.	[18]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Cyclin-dependent kinase 9 (CDK9).	[1]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Cyclin-dependent kinase 9 (CDK9).	[12]

17 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cyclin-dependent kinase 9 (CDK9).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cyclin-dependent kinase 9 (CDK9).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cyclin-dependent kinase 9 (CDK9).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cyclin-dependent kinase 9 (CDK9).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Cyclin-dependent kinase 9 (CDK9).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Cyclin-dependent kinase 9 (CDK9).	[7]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Cyclin-dependent kinase 9 (CDK9).	[8]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the expression of Cyclin-dependent kinase 9 (CDK9).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cyclin-dependent kinase 9 (CDK9).	[10]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Cyclin-dependent kinase 9 (CDK9).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Cyclin-dependent kinase 9 (CDK9).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cyclin-dependent kinase 9 (CDK9).	[13]
BMS-3870032	DMCWIBU	Preclinical	BMS-3870032 decreases the activity of Cyclin-dependent kinase 9 (CDK9).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cyclin-dependent kinase 9 (CDK9).	[15]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Cyclin-dependent kinase 9 (CDK9).	[7]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of Cyclin-dependent kinase 9 (CDK9).	[16]
Wogonin	DMGCF51	Investigative	Wogonin decreases the activity of Cyclin-dependent kinase 9 (CDK9).	[17]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Cdk9 regulates neural differentiation and its expression correlates with the differentiation grade of neuroblastoma and PNET tumors. Cancer Biol Ther. 2005 Mar;4(3):277-81. doi: 10.4161/cbt.4.3.1497. Epub 2005 Mar 20.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [8] Elucidating progesterone effects in breast cancer: cross talk with PDGF signaling pathway in smooth muscle cell. J Cell Biochem. 2007 Jan 1;100(1):174-83. doi: 10.1002/jcb.21045.
• [9] Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells. Chem Biol Interact. 2015 Dec 5;242:107-22.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [12] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] Characterization of molecular and cellular functions of the cyclin-dependent kinase CDK9 using a novel specific inhibitor. Br J Pharmacol. 2014 Jan;171(1):55-68. doi: 10.1111/bph.12408.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.
• [17] Wogonin alleviates BaP-induced DNA damage and oxidative stress in human airway epithelial cells by dual inhibiting CYP1A1 activity and expression. Environ Toxicol. 2023 Nov;38(11):2717-2729. doi: 10.1002/tox.23907. Epub 2023 Jul 29.
• [18] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.